Method for controlling the coagulation of blood by administering epsilon amino caproic acid and heparin



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3,457,347 Patented July 22, 1969 ice METHOD FOR CONTROLLING THE COAGULA-TION OF BLOOD BY ADMINISTERING EPSILON AMINO CAPROIC ACID AND HEPARINJeanette L. Rubricius, Jamaica, N.Y., assignor to Harry H. Le Veen,Jamaica, N.Y. No Drawing. Filed Nov. 22, 1965, Ser. No. 509,211 Int. Cl.A61k 17/18 US. Cl. 424-183 6 Claims ABSTRACT OF THE DISCLOSURE Theadministration of heparin is improved by simultaneously administeringepsilon aminocaproic acid.

This invention relates to methods and materials for controlling clottingcharacteristics of blood. More particularly, this invention relates tomethods and materials useful in safely preventing extension of internalclotting while simultaneously preventing the breaking loose or generaldissolution of clots once formed.

Anticoagulants, such as dicoumarol and heparin, constitute a well knownclass of medical agents, which delay clotting time by inhibiting thelay-down of fibrin. These materials, such as heparin and discoumarol,are routinely used under certain circumstances. However, certainundesirable complications may arise due to the use of anticoagulants.

Of the commonly used anticoagulants, heparin is generally considered themost useful and practical. Heparin therapy has been limited in itsutility by a number of heretofore unsolved complications associated withits application. These complications are of such a frequent and seriousnature that a number of medical experts in many instances have advisedagainst heparin treatment. Examples of such complications are woundinfections, severe hemorrhaging and embolization.

It is therefore one object of this invention to provide methods andmaterials which will obviate the problems associated with the use ofanticoagulant therapy. Another object is to provide a method which willrender anticoagulants safer for postoperative therapy. A further objectis to provide a composition which, when administered to patients, willhave the beneficial effects associated with anticoagulants without thecorresponding detrimental efiects. Another object is to provide such acomposition which can be safely administered to patients having ahistory of thrombophlebitis or varicose veins. A still further objectshall be to provide a method of utilizing an agent which can beadministered separately from but simultaneously with an anticoagulantand which will obviate or alleviate problems associated with the use ofthe anticoagulant.

These and other objects which shall become apparent from the followingdescription are accomplished by the use of an epsilon aminocaproic acid.

Epsilon amino-n-caproic acid is known to be useful in cases ofhyperfibrinolysis to inhibit plasmin and to inhibit activation ofplasmin from US. Patent No. 2,939,- 817. Lysine, or alpha, epsilondiaminocaproic acid behaves similarly.

Plasmin, or fibrinolysin, has been recommended as an alternative toheparin for preventing intravascular thrombosis. In fact, fibrinolysinis considered by some as superior to heparin for this purpose and stillothers have suggested the use of both heparin and fibrinolysin intreating intravascular thrombosis. In accordance with the presentinvention, however, it has been found that the use of an epsilonaminocaproic acid which was a known inhibitor of fibrinolysin, incombination with anticoagulants such as heparin results in theelimination of the problems heretofore associated with the use ofanticoagulants.

It has been discovered that embolization which may result with the useof an anticoagulant is avoided by the simultaneous administration of theaminocaproic acid. The expression simultaneous administration asreferred to herein and in the appended claims describes anadministration such that the effects of the anticoagulant and the aminocaproic acid occur within the host simultaneously. Generally, accordingto the present invention, the anticoagulant is administered parenterallywhile the epsilon aminocaproic acid can be administered in combinationwith the heparin or in a separate injection or separately by oraladministration, for example in tablet or syrup.

Although in the broader aspects of the invention epsilon aminocaproicacids such as lysine may be utilized, in a particularly usefulembodiment of the invention epsilonamino-n-caproic acid is the additivewhich renders anticoagulants such as heparin safe therapeutic agents insituations where anticoagulant therapy otherwise would be dangerousbecause of the aforementioned complications. The effectiveness ofepsilon-amino-n-caproic acid (EACA) in heparin therapy is indeedsurprising since EACA is known as a blood coagulant or clotting promoterand would be expected to negate the known anticoagulant properties ofheparin. With respect to the use of EACA, it is to be noted that,heretofore, the acid is useful only in cases of hyperfibrinolysis. Inaccordance with the present invention, however, plasmin content of theblood treated is usually quite normal. Accordingly, it is consideredpart of the present invention to utilize EACA for patients having normalor even sub-normal plasmin activity.

The following examples, although not intended to in any way limit thescope of the invention, will serve to illustrate the beneficial resultsobtained by the invention. In each of the Examples I through IV below,the therapy has been utilized with more than 50 human beings.

Example I In thrombophlebitis, it is desirable to prevent propagation ofthrombosis. Heparin is the usual form of therapy. There is, however, adanger in using heparin where thrombi are already present because of theembolism known to occur with heparin therapy. According to thisinvention, epsilon amino n caproic acid has been found to be compatiblewith heparin and can either be given together with heparin in the samesolution or independently. Both techniques have been used. When thecompounds were mixed, 500 mgm. of EACA were mixed with 50 mgm. ofheparin. The usual dosage intravenously was 50 mgm. of heparin every 4hours and 500 mgm. of EACA every 4 hours. EACA was administered bymouth. Where the heparin was given separately in dosage of 50 mgm. every4 hours either intravenously or subcutaneously, the EACA was given 500mgm. every 4 hours by mouth.

The present composition and method was applied to over 50 human clinicalcases of thrombophlebitis. The EACA-heparin combination prevented theunwanted embolism often associated with normal heparin therapy andprevented extension and complication of the thrombophlebitis.

Example II During vascular surgery, cross clamping of the aorta or largevessels is often required. When this is done, there is a hazard ofthrombi forming beneath the clamp in the occluded vessel. For thatreason, it is standard practice to administer 50 mgm. of heparinintravenously at the time the aorta is cross clamped. This, however,increases the risk of embolization and wound hemorrhage and infectiondue to clot dissolution. Therefore, according to 3 this invention, EACAin dose of 500 mgm. was administered for every 50 mgm. of heparin givenintravenously. This treatment precluded clot formation beneath the clampand, although post-surgical bleeding time was slightly prolonged, clotsonce formed were not susceptible to dissolution.

Example III Following vascular surgery, heparin is frequently used toprevent thrombosis in the recently operated vessels. There is, however,increased hemorrhage into the wound which causes hematoma and woundinfection, therefore often requiring discontinuance of heparin therapy.This was obviated by the administration of EACA concomitant withheparin. The dosage used was 50 mgm. of heparin intravenously every 4hours together with 500 mgm. of EACA.

Example IV Patients who have had pulmonary emboli either postoperativelyor spontaneously without evidence of thrombophlebitis are often treatedwith heparin or vena cava ligation or both. These, however, increase theprobability of other thrombi breaking loose. To obviate this problem,the following regime was employed: Vena cava ligation was doneimmediately after the embolization occurred. Heparin, 50 mgm. every 4hours, together with EACA, 500 mgm. every 4 hours, was administeredintravenously in the post-operative period for approximately 2 or 3weeks after surgery. The dosage scale employed was approximately 10parts by weight EACA to one part heparin. This dosage scale may besomewhat high, and it was found that doses as low as 250 mgm. of EACAfor every 50 mgm. of heparin would give satisfactory results. In otherwords, the dosage schedule varies somewhat between 5 and parts EACA to 1part heparin. The treatment obviated any complications due to furtherembolization.

Example V To investigate the cause of bleeding following heparintherapy, an experiment was performed on 25 rabbits. A longitudinalincision was made into the vena cava to produce what would be a fatalhemorrhage. This hemorrhage was controlled by the application of gelatinfoam with pressure to obturate the bleeding site. After 5 minutes afibrin clot was formed in the gelatin foam and the bleeding wascontrolled. The fibrin seal was sufiicient to prevent further bleeding.The animals were thereafter placed on heparin therapy. Fourteen of thetwenty-five animals succumbed to fatal hemorrhage. The fibrin networkwhich had held the gelatin foam to the opening in the venacava hadundergone lysis.

Example VI The same procedure as in Example V was followed except thatthe animals were given epsilon-amino-n-caproic acid along with theheparin therapy. Fatal hemorrhage occurred in only three animals. Thisfigure compared favorably to a control group of animals of which neitherheparin nor epsilon-amino-n-caproic acid were administered.

Example VII The same procedure as in Example V was followed except thatthe animals were given lysine along with the heparin therapy. Only threeanimals succumbed to fatal hemmorrhage.

Example VIII Vena caval thrombosis was produced by chemical means infourteen healthy mongrel dogs. After production of the thrombus, i.e.about live days after the operation, seven animals were treated withheparin while the other seven were treated with heparin in conjunctionwith E-amino-n-caproic acid. In those animals receiving only heparin,the thrombus became free floating and eventually embolized. In theremaining seven, no free floating thrombi developed and no embolismoccurred. In each case the heparin was administered by intravascular inadmixture with the heparin solution and orally by addition to thedrinking Water.

Microscopic studies confirmed that in the animals treated with heparinalone each clot lacked cellularity and organization, while in theEACA-heparin treated animals each clot was highly cellular andorganized.

As indicated above, this invention provides efficacious results incombating a number of specific problems associated with heparin therapy.The dosages of the epsilon amino caproic acid to be administered dependon the specific problem to be avoided as well as the size etc. of theindividual to be treated. Generally the EACA to heparin ratio should becontrolled at about 5-30 parts EACA to 1 part heparin (parts hereinrefer to parts by Weight), whereas a particularly effective rangeappears to be 5-10 parts EACA to one part heparin.

Although the maximum dosage of EACA can be as high as 30 gm. per day,generally the dosage is not over 15 grams and the particularly usefuldosage for this invention does not exceed about 3-4 gm. in 24 hours ofabout 500 milligrams every four hours. Indications are that as little as250 mg. of EACA will give beneficial results during heparin therapy. Theheparin dosage does not generally exceed 450 milligrams per day, but thedosage is again determined by the particular problem and patient beingtreated and as little as 50 milligram dosage has been shown to beeffective.

The administration of the heparin can be carried out in generallyaccepted methods usually involving intravenous injections of a glucoseand/or saline solution of a suitable pharmaceutical carrier containingabout 50-150 mgm. of heparin per liter of solution. The EACA can beadded directly to the heparin solution, injected separately by solutionof a suitable pharmaceutical carrier in a concentration of about 250mg./cc., or, as previously mentioned, administered orally in the form oftablets, syrup etc. The administration is often initiated by a primingdosage of heparin and EACA followed by smaller doses at periodicintervals. Again, the rate of such doses are dependant upon theparticular circumstances involved, but a particularly useful rateinvolves a primwing dosage of l50 mgm. of heparin followed by 50 mgm.every four hours; the EACA being simultaneously added in the ratio of5-10 parts EACA to one part heparin. The dosage can, however, also be bya gradual administration over a period of time, eg by instillation.

The solutions of this invention for injection or syrups etc. for oraladministration can contain additional quantities of other normallyaccepted therapeutic agents, e.g. sedatives, anesthetics, etc., even insomewhat large quantities, the prime limitation being the compatibilityof the additive with heparin and/or the epsilon amino caproic acid.

What is claimed is:

1. A method of avoiding wound hemorrhage or embolization during heparintherapy in patients having normal or sub-normal plasmin activity whichcomprises the simultaneous administration of epsilon aminocaproic acidand heparin wherein the heparin is administered parenternally and theepsilon aminocaproic acid is simultaneously administered eitherparenternally or orally in an amount of from 250 mg. to 30 grams per dayand wherein said epsilon aminocaproic acid is administered in an amountof from 5 to 30 parts by weight of heparin.

2. A method according to claim 1 wherein said heparin and epsilonaminocaproic acid are administered together as a mixture.

3. A method according to claim 1 wherein said heparin and epsilonaminocaproic acid are administered separately.

4. A method according to claim 1 wherein said amount is from 5 to 10parts by weight per part by weight of heparin.

5. A method according to claim 1 wherein the acid is epsilonarnino-n-caproic acid.

6. A method according to claim 1 wherein the acid is alpha, epsilondiaminocaproic acid.

References Cited UNITED STATES PATENTS 6/1960 Nagasawa et a1 167-65OTHER REFERENCES Lederle, Amicar, March 1964. The Journal ofBiochemistry, The Inhibition of Plas- 6 min by Some Amino AcidDerivatives, Nagamatsu, A. et a1. vol. 54, pp. 491-496, 1963.

Acta Physiologica Scandinavia, The Effect of Heparin and e-AminocaproicAcid, etc., Johansson, B. et al., pp. 267-77; March 1964.

ALBERT T. MEYERS, Primary Examiner HOWARD M. ELLIS, Assistant ExaminerUs. 01. X.R.

